This is an ongoing project, in which the biochemical mechanisms underlying enzyme regulation in differentiating tissues are under investigation. Mechanisms of controls of the initial emergence of enzymes and their subsequent developmental courses will be under study, with hope of contributing to the understanding of genetic and developmental abnormalities in man. The postnatal development of histidase (L-histidine ammonia-lyase) in the rat serves as the principal model system. This enzyme initially appears in liver and epidermis following parturition; rates of histidase biosynthesis and resultant accumulation of catalytically active enzyme protein undergo further complex developmental courses specific to each tissue and sex. We have already demonstrated that histidase biosynthetic rate, level and catalytic activity are positively and negatively responsive to several hormonal stimuli. Furthermore, certain of these hormones have been shown to participate in effecting alterations in histidase at specific postnatal developmental stages. We now plan to probe further into the intimate mechanisms underlying these hormonal influences during peri- and postnatal development of histidase in liver and epidermis. This will be accomplished by: determining whether developmental and hormonal induced alterations in skin histidase are due to shifts in cell populations or alterations in biosynthetic rates of histidase containing cells; investigating, in depth, the mechanisms of hypophyseal inhibition of hepatic histidase levels and its relationship with estrogenic induction of this enzyme; continuing our studies on direct hormonal effects on hepatocytes in the regulation of this enzyme in in vitro systems; exploring the mechanisms of histidase development and hormonal control at the level of differential gene expression, by measurement of specific histidase mRNA levels; initiating studies on influences of maternal mal-nourishment prior to and during pregnancy and possible "imprinting" effects of neonatal endocrine manipulation on subsequent postnatal development of histidase and other enzymes, in order to explore parameters responsible for postnatal metabolic incompetence.